Submissions for variant NM_000545.8(HNF1A):c.155_156delinsCT (p.Gly52Ala)

dbSNP: rs587778393

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Monogenic Diabetes Variant Curation Expert Panel	RCV002250358	SCV002520654	benign	Monogenic diabetes	2022-05-02	reviewed by expert panel	curation	The c.155_156delinsCT variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of Glycine to Alanine at codon 52 (p.(Gly52Ala)) of transcript NM_000545.8. This variant has a Popmax Filtering allele frequency in gnomAD 2.1.1 of 0.0024, which is greater than the MDEP threshold for BA1 (greater than or equal to 0.0001) (BA1). In summary, c.155_156delinsCT meets the criteria to be classified as benign for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/2021): BA1.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001393910	SCV001595587	likely benign	not provided	2024-01-04	criteria provided, single submitter	clinical testing
GeneDx	RCV001393910	SCV001803928	likely benign	not provided	2020-12-15	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 10690959, 25555642, 23348805, 24728327)
Genetic Services Laboratory, University of Chicago	RCV000121186	SCV002069042	uncertain significance	not specified	2017-11-22	criteria provided, single submitter	clinical testing
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV002399487	SCV002605557	likely benign	Maturity onset diabetes mellitus in young		criteria provided, single submitter	research	Mutations in HNF1A gene can predispose to MODY3. It is associated with both micro and macrovascular complications of diabetes, especially cardiovascular complications. Associated with glucosuria. May respond well to sulfonylureas. Sufficient evidence is found to confer the association of this particular variant rs587778393 with MODY3.
Ambry Genetics	RCV002399487	SCV002709423	uncertain significance	Maturity onset diabetes mellitus in young	2016-11-08	criteria provided, single submitter	clinical testing	The c.155_156delGCinsCT variant (also known as p.G52A), located in coding exon 1 of the HNF1A gene, results from an in-frame deletion of GC and insertion of CT at nucleotide positions 155 to 156. This results in the substitution of the glycine residue for an alanine residue at codon 52, an amino acid with similar properties. Based on data from the Exome Aggregation Consortium (ExAC), the c.155_156delGCinsCT allele has an overall frequency of approximately 0.03% of total alleles studied, having been observed in 0.3% African alleles. In a study of African American families with type 2 diabetes, this alteration was present in two siblings with the disease as well as in their non-diabetic sibling (Elbein SC et al. Metab. Clin. Exp., 2000 Feb;49:280-4). In a study of 586 individuals with auto-antibody negative diabetes diagnosed before age 20, the p.G52A alteration (resulting from c.155G>C) was described in one individual; however, family history of diabetes was not part of the inclusion criteria and 20% of the patients positive for MODY alterations were African American (Pihoker C et al. J. Clin. Endocrinol. Metab., 2013 Oct;98:4055-62). This amino acid position is well conserved in available vertebrate species. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000121186	SCV005040312	likely benign	not specified	2024-03-14	criteria provided, single submitter	clinical testing	Variant summary: HNF1A c.155_156delinsCT (p.Gly52Ala) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00027 in 269658 control chromosomes. The observed variant frequency is approximately 11 fold of the estimated maximal expected allele frequency for a pathogenic variant in HNF1A causing Maturity Onset Diabetes Of The Young 3 phenotype (2.5e-05), strongly suggesting that the variant is benign. c.155_156delinsCT has been reported in the literature in individuals affected with Maturity Onset Diabetes Of The Young 3 (Elbein_2000, Bennett_2014) without evidence for causality. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 10690959, 25555642). ClinVar contains an entry for this variant (Variation ID: 134503). Based on the evidence outlined above, the variant was classified as likely benign.
ITMI	RCV000121186	SCV000085354	not provided	not specified	2013-09-19	no assertion provided	reference population
PreventionGenetics, part of Exact Sciences	RCV003892112	SCV004708611	likely benign	HNF1A-related disorder	2023-02-28	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).